Alkylaminoalkyl-sulfonyl-terminated Beta-alanineamide amino-diol compounds for treatment of hypertension

ABSTRACT

Compounds characterized generally as alkylaminoalkyl-terminated β-alanineamide amino diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of the formula  
                 
 
     wherein n is two or three; wherein x is a number selected from zero, one and two; wherein R 2  is selected from hydrido, methyl, ethyl and phenyl; wherein R 3  is selected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl, napthylmethyl, fluoronaphthylmethyl and chloronaphthylmethyl; wherein R 5  is methyl; wherein R 7  is cyclohexylmethyl; wherein R 8  is selected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; and wherein each of R 9  and R 10  is a group independently selected from methyl, ethyl and isopropyl; or a pharmaceutically-acceptable salt thereof.

FIELD OF THE INVENTION

[0001] Renin-inhibiting compounds are known for control of hypertension.Of particular interest herein are compounds useful as renin inhibitingagents.

BACKGROUND OF THE INVENTION

[0002] Renin is a proteolytic enzyme produced and secreted into thebloodstream by the juxtaglomerular cells of the kidney. In thebloodstream, renin cleaves a peptide bond in the serum proteinangiotensinogen to produce a decapeptide known as angiotensin I. Asecond enzyme known as angiotensin converting enzyme, cleavesangiotensin I to produce the octapeptide known as angiotensin II.Angiotensin II is a potent pressor agent responsible forvasoconstriction and elevation of cardiovascular pressure. Attempts havebeen made to control hypertension by blocking the action of renin or byblocking the formation of angiotensin II in the body with inhibitors ofangiotensin I converting enzyme.

[0003] Classes of compounds published as inhibitors of the action ofrenin on angiotensinogen include renin antibodies, pepstatin and itsanalogs, phospholipids, angiotensinogen analogs, pro-renin relatedanalogs and peptide aldehydes.

[0004] A peptide isolated from actinomyces has been reported as aninhibitor of aspartyl proteases such as pepsin, cathepsin D and renin[Umezawa et al, in J. Antibiot. (Tokyo), 23, 259-262 (1970)]. Thispeptide, known as pepstatin, was found to reduce blood pressure in vivoafter the injection of hog renin into nephrectomized rats [Gross et al,Science, 175, 656 (1971)]. Pepstatin has the disadvantages of lowsolubility and of inhibiting acid proteases in addition to renin.Modified pepstatins have been synthesized in an attempt to increase thespecificity for human renin over other physiologically importantenzymes. While some degree of specificity has been achieved, thisapproach has led to rather high molecular weight hepta- and octapeptides[Boger et al, Nature, 303, 81 (1983)]. High molecular weight peptidesare generally considered undesirable as drugs because gastrointestinalabsorption is impaired and plasma stability is compromised.

[0005] Short peptide aldehydes have been reported as renin inhibitors[Kokubu et al, Biochim. Biophys. Res. Commun., 118, 929 (1984); Castroet al, FEBS Lett., 167, 273 (1984)]. Such compounds have a reactiveC-terminal aldehyde group and would likely be unstable in vivo.

[0006] Other peptidyl compounds have been described as renin inhibitors.EP Appl. #128,762, published Dec. 18, 1984, describes dipeptide andtripeptide glyco-containing compounds as renin inhibitors [also seeHanson et al, Biochm. Biophys. Res. Comm., 132, 155-161 (1985), 146,959-963 (1987)]. EP Appl. #181,110, published May 14, 1986, describesdipeptide histidine derivatives as renin inhibitors. EP Appl. #186,977published Jul. 9, 1986 describes renin-inhibiting compounds containingan alkynyl moiety, specifically a propargyl glycine moiety, attached tothe main chain between the N-terminus and the C-terminus, such asN-[4(S)-[(N)-[bis(1-naphthylmethyl)acetyl]-D,L-propargylglycylamino]-3(S)-hydroxy-6-methylheptanoyl]-L-isoleucinol.EP Appl. #189,203, published Jul. 30, 1986, describespeptidyl-aminodiols as renin inhibitors. EP Appl. #200,406, publishedDec. 10, 1986, describes alkylnaphthylmethylpropionylhistidylaminohydroxy alkanoates as renin inhibitors. EP Appl. #216,539,published Apr. 1, 1987, describes alkylnaphthylmethylpropionyl aminoacylaminoalkanoate compounds as renin inhibitors orally administered fortreatment of renin-associated hypertension. PCT Application No. WO87/04349, published Jul. 30, 1987, describes aminocarbonyl aminoacylhydroxyether derivatives having an alkylamino-containing terminalsubstituent and which are described as having renin-inhibiting activityfor use in treating hypertension. EP Appl. #300,189 published Jan. 25,1989 describes amino acid monohydric derivatives having analkylaminoalkylamino N-terminus and a β-alanine-histidine orsarcosyl-histidine attached to the main chain between the N-terminus andthe C-terminus, which derivatives are mentioned as useful in treatinghypertension. U.S. Pat. No. 4,902,706 which issued Feb. 13, 1990describes a series of histidineamide-containing aminoalkylaminocarbonyl-N-terminal aminodiol derivatives for use as renininhibitors. U.S. Pat. No. 5,032,577 which issued Jul. 16, 1991 describesa series of histidineamide-aminodiol-containing renin inhibitors.

[0007] Several classes of sulfonyl-containing amino-diol renin-inhibitorcompounds are known. For example, EP #229,667 published Jul. 22, 1987describes generally alkylsulfonyl histidineamide amino diolC-terminated-alkyl compounds as renin inhibitors. Australian PatentApplication #30797/89 published Sep. 7, 1989 describes alkylsulfonylhistineamide amino diol C-terminated-alkyl compounds as renininhibitors, such as (S)-α-[(S)-α-[(t-butyl-sulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4,4-dimethylpentyl]-imidazole-4-propionamideand (S)-α-[(S)-α-[(t-butylsulphonyl)methyl] hydrocinnamamido]-N-[(1S,2R,3S,4RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylhexyl]imidazole-4-propionamide.U.S. Pat. No. 4,914,129 issued Apr. 3, 1990 describes sulfone-containingamino-hydroxyvaleryl compounds for use as antihypertensive agents, suchas the compoundsN-[2(S)-benzyl-3-tert-methylsulfonylpropionyl]-His-Cha-Val-n-butylamideand N-[2(R)-benzyl-3-tert-methylsulfonylpropionyl]-His-Cha-Val-n-butylamide. EP #416,373 published Mar. 13, 91 describesalkylsulfonyl histidineamide amino diol compounds as renin-inhibitors,such as (S)-α-[(S)- α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazol-4-propionamideand (S)-α-[(S)-α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3R/S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxybutyl]imidazol-4-propionamide.

[0008] Alkylaminoalkyl-terminated amino-diol renin-inhibitor compoundsare known. For example, U.S. Pat. No. 4,900,745 to Hanson et al whichissued Feb. 13, 1990 describes poly(aminoalkyl)aminocarbonyl amino-diolamino acid derivatives as antihypertensive agents such asO-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-α-(R)-ethyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane andO-{N-[2-{N-[2-{N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-leucineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. U.S. Pat.No. 4,902,706 to Hanson et al which issued Feb. 20, 1990 describesaminoalkylaminocarbonyl amino-diol amino acid derivatives asantihypertensive agents such as O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-α -(R)-ethyl-β-alanineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane andO-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl-3-L-phenyllactyl-L-leucineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.

[0009] Beta-amino-acid-containing amino-diol compounds have beendescribed as renin inhibitors. For example, U.S. Pat. No. 4,900,746 toHanson et al which issued Feb. 13, 1990 describes ethereal N-terminalaminodiol amino acid derivatives as antihypertensive agents such asO-[N-methyl-N-(2-methoxyethyl)aminocarbonyl]-3-L-homophenyllactyl-α-(R)-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. U.S. Pat.No. 4,931,429 which issued Jun. 5, 1990 describesα-aminoacyl-β-aminoacyl aminodiols as antihypertensive agents such asBoc-L-phenylalaninyl-D,L-α -methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. U.S. Pat.No. 5,089,471 which issued Feb. 18, 1992 describes peptidyl β-aminoacylaminodiol carbamates as antihypertensive agents such asO-(N-morpholinocarbonyl)-3-L-phenyllactyl-α-(R)-methyl-β-alaninamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.

DESCRIPTION OF THE INVENTION

[0010] Alkylaminoalkyl-sulfonyl-terminated β-alanine amino diolcompounds, having utility as renin inhibitors for treatment ofhypertension in a subject, constitute a family of compounds of generalFormula I:

[0011] wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein n is a numberselected from zero through five, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom linear and branched alkyl groups containing from one to about fourcarbon atoms; wherein R⁷ is a group selected from alkyl, cycloalkylalkyland aralkyl; wherein R⁸ is a group selected from hydrido, alkyl,hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and haloalkenyl;wherein each of R⁹ and R¹⁰ is a group independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl, aryl, aralkyl,haloaryl and haloaralkyl; and wherein any one of said R¹ through R¹¹groups having a substitutable position may be substituted with one ormore groups selected from alkyl, hydroxy, hydroxyalkyl, halo, alkoxy,alkoxyalkyl and alkenyl; or a pharmaceutically-acceptable salt thereof.

[0012] A preferred family of compounds consists of compounds of FormulaI wherein each of R¹ and R¹¹ is independently selected from hydrido,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl,N,N-diethylaminoethyl and phenyl; wherein n is a number selected fromzero through four, inclusive; wherein x is a number selected from zero,one and two; wherein R² is selected from hydrido and alkyl; wherein R³is selected from hydrido, cycloalkylalkyl, phenylalkyl, halophenylalkyl,naphthylalkyl and halonaphthylalkyl; wherein each of R⁴ and R⁶ isindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom methyl, ethyl, n-propyl, isopropyl and n-butyl; wherein R⁷ isselected from cyclohexylmethyl and benzyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R⁸ is selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, hydroxyalkyl, alkenyl and haloalkenyl; and wherein eachof R⁹ and R¹⁰ is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, alkanoyl, halophenyl, phenylalkyl, halophenylalkyl,naphthyl, halonaphthyl, naphthylalkyl and halonaphthylalkyl; or apharmaceutically-acceptable salt thereof.

[0013] A more preferred family of compounds consists of compounds ofFormula I wherein each of R¹ and R¹¹ is independently selected fromhydrido, methyl, ethyl, n-propyl and isopropyl; wherein n is a numberselected from zero through three, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido,methyl, ethyl and n-propyl; wherein R³ is selected from hydrido,cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl, fluorophenylethyl,chlorobenzyl, chlorophenylethyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is independently selected from hydrido and methyl; wherein R⁵ isselected from methyl, ethyl, n-propyl and isopropyl; wherein R⁷ iscyclohexylmethyl; wherein R⁸ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyland vinyl; and wherein each of R⁹ and R¹⁰ is independently selected fromhydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl,propylcarbonyl, ethylcarbonyl, methylcarbonyl, phenyl, benzyl,phenylethyl, monochlorophenyl, dichlorophenyl, monofluorophenyl,difluorophenyl, monochlorophenylmethyl, monochlorophenylethyl,dichlorophenylmethyl, dichlorophenylethyl, naphthyl, monofluoronaphthyl,monochloronaphthyl, naphthylmethyl, naphthylethyl, fluoronapthylmethyland chloronaphthylethyl; or a pharmaceutically-acceptable salt thereof.

[0014] An even more preferred family of compounds consists of compoundsFormula I wherein each of R¹ and R¹¹ is independently hydrido or methyl;wherein n is a number selected from zero through three, inclusive;wherein x is zero or two; wherein R² is selected from hydrido, methyl,ethyl and n-propyl; wherein R³ is selected from hydrido,cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is hydrido; wherein R⁵ is selected from methyl andethyl; wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected fromethyl, n-propyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl,cyclopropylmethyl, allyl and vinyl; wherein each of R⁹ and R¹⁰ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,cyclopropylmethyl, phenyl, benzyl, monochlorophenyl and dichlorophenyl;or a pharmaceutically-acceptable salt thereof.

[0015] A highly preferred family of compounds consists of compounds ofFormula II:

[0016] wherein n is two or three; wherein x is a number selected fromzero, one and two; wherein R² is selected from hydrido, methyl, ethyland phenyl; wherein R³ is selected from hydrido, cyclohexylmethyl,benzyl, fluorobenzyl, chlorobenzyl, fluoronaphthylmethyl, naphthylmethyland chloronaphthylmethyl; wherein R⁷ is cyclohexylmethyl; wherein R⁸ isselected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyland vinyl; wherein each of R⁹ and R¹⁰ is independently selected frommethyl, ethyl and isopropyl; or a pharmaceutically-acceptable saltthereof.

[0017] The term “hydrido” denotes a single hydrogen atom (H). Thishydrido group may be attached, for example, to an oxygen atom to form ahydroxyl group; or, as another example, one hydride group may beattached to a carbon atom to form a

[0018] group; or, as another example, two hydrido groups may be attachedto a carbon atom to form a —CH₂— group. Where the term “alkyl” is used,either alone or within other terms such as “hydroxyalkyl”, the term“alkyl” embraces linear or branched radicals having one to about twentycarbon atoms or, preferably, one to about twelve carbon atoms. Morepreferred alkyl radicals are “lower alkyl” radicals having one to aboutten carbon atoms. Most preferred are lower alkyl radicals having one toabout six carbon atoms. The term “cycloalkyl” embraces cyclic radicalshaving three to about ten ring carbon atoms, preferably three to aboutsix carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. The terms “alkylol” and “hydroxyalkyl” embrace linear orbranched alkyl groups having one to about ten carbon atoms any one ofwhich may be substituted with one or more hydroxyl groups. The term“alkenyl” embraces linear or branched radicals having two to abouttwenty carbon atoms, preferably three to about ten carbon atoms, andcontaining at least one carbon-carbon double bond, which carbon-carbondouble bond may have either cis or trans geometry within the alkenylmoiety. The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy group. The term “alkoxyalkyl” alsoembraces alkyl radicals having two or more alkoxy groups attached to thealkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylgroups. Preferred aryl groups are those consisting of one, two, or threebenzene rings. The term “aryl” embraces aromatic radicals such asphenyl, naphthyl and biphenyl. The term “aralkyl” embracesaryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenyl-ethyl, phenylbutyl and diphenylethyl. The terms“benzyl” and “phenylmethyl” are interchangeable. Each of the termssulfide, sulfinyl, and “sulfonyl”, whether used alone or linked to otherterms, denotes, respectively the divalent radicals

[0019] The term “alkenylalkyl” denotes a radical having a double-bondunsaturation site between two carbons, and which radical may consist ofonly two carbons or may be further substituted with alkyl groups whichmay optionally contain additional double-bond unsaturation. For any ofthe foregoing defined radicals, preferred radicals are those containingfrom one to about fifteen carbon atoms.

[0020] Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl andalkynyl groups may have one unsaturated bond, such as an allyl group, ormay have a plurality of unsaturated bonds, with such plurality of bondseither adjacent, such as allene-type structures, or in conjugation, orseparated by several saturated carbons.

[0021] Also included in the family of compounds of Formula I areisomeric forms, including diastereoisomers. Compounds of Formula I wouldbe useful to treat various circulatory-related disorders. As usedherein, the term “circulatory-related” disorder is intended to embracecardiovascular disorders and disorders of the circulatory system, aswell as disorders related to the circulatory system such as ophthalmicdisorders including glaucoma. In particular, compounds of Formula Iwould be useful to inhibit enzymatic conversion of angiotensinogen toangiotensin I. When administered orally, a compound of Formula I wouldbe expected to inhibit plasma renin activity and, consequently, lowerblood pressure in a patient such as a mammalian subject (e.g., a humansubject). Thus, compounds of Formula I would be therapeutically usefulin methods for treating hypertension by administering to a hypertensivesubject a therapeutically-effective amount of a compound of Formula I.The phrase “hypertensive subject” means, in this context, a subjectsuffering from or afflicted with the effects of hypertension orsusceptible to a hypertensive condition if not treated to prevent orcontrol such hypertension. Other examples of circulatory-relateddisorders which could be treated by compounds of the invention includecongestive heart failure, renal failure and glaucoma.

Description of the Synthetic Methods for the Preparation of the ReninInhibitors of the Invention

[0022]

Formula I

[0023] wherein R¹ through R¹¹, x and n are as defined above.

[0024] A suitably protected amino aldehyde 1 is treated with a Grignardreagent or other organometallic reagent, preferably vinylmagnesiumbromide, to obtain the vinyl carbinol 2. This material, suitablyprotected, is oxidized, preferably with ozone, followed by dimethylsulfide or zinc treatment, to give intermediate 3. The preceding processis exemplified in Hanson et al, J. Org. Chem., 50, 5399 (1985). Thisaldehyde is reacted with an organometallic reagent such asisobutylmagnesium chloride to give intermediate 4. Compound 4 isdeprotected then coupled, using standard amide/peptide couplingmethodology to protected β-amino acid derivatives 5 to give compound 6.These standard coupling procedures such as the carbodiimide, activeester (N-hydroxysuccinimide), and mixed carbonic anhydride methods areshown in Benoiton et al, J. Org. Chem., 48, 2939 (1983) and Bodansky etal, “Peptide Synthesis”, Wiley (1976). Intermediate 6 is thendeprotected, then coupled to intermediate 7 or 11 or 12 using thestandard amide/peptide coupling methodology, to give compounds ofFormula I. Suitable protecting groups may be selected from among thosereviewed by R. Geiger in “The Peptides”, Academic Press, N.Y. vol. 2(1979). For example, P₁ or P₃ may be Boc or Cbz; P₂ may be a typicaloxygen protective group such as acetyl or t-butyldimethylsilyl.

[0025] wherein R¹ through R³, R⁹ through R¹¹ and n are as defined aboveand R is lower alkyl or benzyl.

[0026] Intermediate 7 may be prepared according to Synthetic Scheme 2.The addition of thiol 9 to an acrylic ester 8 in the presence of basecatalysts such as sodium hydroxide, triethylamine orbenzyltrimethylammonium hydroxide, afforded the α,β disubstitutedpropanoic ester 10. Compound 10 is converted into its correspondingpropanoic acid 11 via alkaline hydrolysis. Compound 10 may be convertedto either sulfone 7 or sulfoxide 12 via a two step process: oxidationwith 3-chloroperbenzoic acid (for 12) or potassium peroxomonsulfate (for7), followed by alkaline hydrolysis or hydrogenolysis (when R=benzyl).

[0027] Abbreviations: P₁ is an N-protecting group; P₂ is H or an oxygenprotecting group; P₃ is an N-protecting group.

[0028] The following Steps 1-14 constitute specific exemplification ofmethods to prepare starting materials and intermediates embraced by theforegoing generic synthetic schemes. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thecompounds of Steps 1-14. All temperatures expressed are in degreesCentigrade. Compound of Example 1 was prepared by using the proceduresdescribed in the following Steps 1-14:

[0029] Step 1: Preparation of(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal

[0030] Ozone/oxygen was bubbled at −70° C. into a solution of(3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene(2.55 g, 8.0 mmol) [prepared by the method of Hanson et al, J. Org.Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deepblue color persisted. Oxygen was introduced until the blue colorcompletely faded, then 3.0 mL of Me₂S was added and the solution wasallowed to warm to 0-5° C. and stand overnight. The solvent was removedat 0° C. under vacuum yielding the title compound as a thick yellow oilwhich was used in the following step without purification.

[0031] Step 2: Preparation of (2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane

[0032] The oil prepared in Step 1 was dissolved under nitrogen in 100 mLof dry THF and cooled to −70° C. To this solution was added 13 mL (26mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and thestirred mixture was allowed to warm to room temperature and stir for 2hrs. After decomposition with MeOH/H₂O the mixture was diluted withether, washed with saturated NH₄Cl solution twice, then dried and thesolvents stripped off under vacuum. The residue was allowed to standovernight in 80% MeOH—H₂O containing excess ammonium hydroxide. The MeOHwas stripped off and the mixture was extracted with ether. Theseextracts were combined, washed with water, dilute KHSO₄, then dried andevaporated to give 2.36 g of a yellow glass which crystallized from 50mL of pentane on standing overnight. The yellow-white powder obtainedwas recrystallized from ether-hexane and furnished the title compound(0.41 g) as white, hairy needles, mp 134-136° C., Rf (ether): singlespot, 0.6. By chromatography of the mother liquors and crystallizationof the appropriate fractions, an additional 0.22 g of product, mp138-139° C., was obtained. Anal: Calcd. for C₁₉H₃₁NO₄ (337.45): C,67.62; H, 9.26; N, 4.15. Found: C, 67.51; H, 9.43; N, 4.24.

[0033] Step 3: Preparation of (2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0034] The diol of Step 2, 0.27 g, was reduced in MeOH with 60 psi H₂ at60° C. in 3 hrs using 5% Rh/C catalyst. After filtering, the solvent wasstripped off and the white crystals were recrystallized fromCH₂Cl₂-hexane to furnish tiny needles of the title compound, 0.19 g, mp126-128° C.; further recrystallization gave mp 128.5-129.5° C. Rf(ether): single spot, 0.8. Anal: Calcd. for C₁₉H₃₇NO₄ (343.50): C,66.43; H, 10.86, N, 4.08. Found: C, 66.43; H, 11.01; N, 4.03.

[0035] Step 4: Preparation of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0036] The title compound of Step 3 (10 g) was dissolved 6.9N HCl indioxane (300 mL). The mixture was stirred for 30 minutes at roomtemperature. The solvent was removed in vacuo and to the residue wasadded 5% aqueous sodium hydroxide (30 mL) until a pH of 14 was obtained.This mixture was extracted with ether and the ether extract was washedwith water and brine, then the solvent was evaporated to give the titlecompound (7.3 g, 100% yield). ¹H NMR: 300 MHz spectrum consistent withproposed structure. Anal: calcd. for C₁₄H₂₉NO₂: C, 69.07; H, 12.01; N,5.78. Found: C, 69.19; H, 12.34; N, 5.78.

[0037] Step 5: Preparation of N-Boc-α-(R)-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0038] To a solution of N-Boc-α-(R,S)-methyl-β-alanine (137 mg, 0.67mmol) in methylene chloride (4 mL) at −10° C. was addedN-methylpiperidine (61 mg, 0.61 mmol) followed by isobutylchloroformate(75 mg, 0.55 mmol). After stirring for 5 min., a solution of the amineof Step 4 in methylene chloride (2 mL) was added. The resulting solutionwas stirred for 3 hours at −10° C., followed by 2 hours at roomtemperature at which time a white solid was isolated by filteration (60mg, 34% yield): Rf=0.3 (5% MeOH/methylene chloride, silica gel); mp197-200°; ¹H NMR (CDCl₃): consistent with proposed structure. Anal:Calc'd for C₂₃H₄₄N₂O₅+0,25 H₂O: C, 63.77; H, 10.35; N, 6.46. Found: C,63.84; H, 10.50; N, 6.45.

[0039] Step 6: Preparation of α-(R)-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0040] The title compound of Step 5 (53 mg, 0.12 mmol) was stirred witha mixture of trifluoroacetic acid and methanol (9:1, 5 mL). Theresulting solution was allowed to stand at room temperature for 20minutes, then the solvent was evaporated. The resulting oil was stirredfor 2 hours with aqueous potassium carbonate (5%, 10 mL). This mixturewas then .extracted with ethyl acetate which was dried, filtered andevaporated to give the title compound (40 mg, 100%): Rf: 0.10 (5%MeOH/methylene chloride, silica gel). This material was used withoutfurther purification.

[0041] Step 7: Preparation of ethyl α-methylenebenzenepropanoate

[0042] A mixture of of KOH (8.5 g) in ethanol (100 mL) was added at roomtemperature to benzylmalonic acid diethyl ester (40 g) in ethanol (80mL) and the whole was stirred at room temperature overnight, thenconcentrated by evaporation, thereafter water (14 mL) was added and thenthe mixture was acidified in an ice bath with concentrated hydrochloricacid (12.6 mL). Partitioning between water and ether was carried out,the organic phase was dried and the ether was distilled off. Then,pyridine (26 mL), piperidine (1.22 g) and paraformaldehyde (3.56 g) wereadded to the residue. The mixture was heated in an oil bath (130° ) for90 minutes, cooled, water (440 mL) were added and extraction was carriedout 3 times with n-hexane (150 mL). The combined organic phases werewashed successively with water, 1N HCl, water, saturated NaHCO₃ solutionand brine. The solution was dried (MgSO₄) and evaporated to give thetitle compound as colorless oil (26 g, 85% yield). ¹H NMR: 300 MHzspectrum consistent with proposed structure.

[0043] Step 8: Preparation of α-methylenebenzenepropanoic acid

[0044] The ethyl α-methylenebenzenepropanoate of Step 7 (4.6 g, 24.3mmol) was dissolved in methanol (12 mL) and then reacted with 2Npotassium hydroxide (24 mL) solution. The mixture was stirred at roomtemperature for 4 hours and concentrated by evaporation. The residue wasdiluted with water and washed with ether. The aqueous layer wasacidified to pH 2 with 1N HCl, and then extracted with ethyl acetate.The extracts were dried (Na₂SO₄) and evaporated to give the titlecompound as colorless oil (2.8 g, 66% yield). ¹H NMR: 300 MHz spectrumconsistent with proposed structure.

[0045] Step 9: Preparation of phenylmethyl α-methylenebenzenepropanoate

[0046] The title acid of Step 8 (5.2 g, 30 mmol) was dissolved indimethylformamide (25 mL) and cooled to 0° C. To this potassiumcarbonate (5.7 g, 41.48 mmol) was added followed by benzyl bromide (5.7g, 29.7 mmol). The mixture was stirred at room temperature overnight.The mixture was filtered and the filtrate was diluted with ethylacetate, washed with 3 times of water, brine. The solution was dried(Na₂SO₄) and evaporated. The residue was purified by flashchromatography on silica gel, eluting with 90:10 heptane:ethyl acetateto give the pure title compound as yellow oil (4.5 g, 60% yield). ¹HNMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd.for C₁₇H₁₆O₂: C, 80.93; H, 6.39. Found: C, 80.69; H, 6.47.

[0047] Step 10: Preparation of phenylmethylα-[[[2-(dimethylamino)ethyl]thio]methyl]benzenepropanoate

[0048] The oil prepared in Step 9 (1.5 g, 5.95 mmol) was dissolved underargon in methanol (22 mL). To this solution was added2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine(0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6mmol), and the mixture was stirred at room temperature for 16 hours. Thesolvent was removed on a rotary evaporator and then the residue waspurified by flash chromatography on silica gel, eluting with 20:1CH₂Cl₂:MeOH to give the pure title compound (0.5 g, 24% yield). ¹H NMR:300 MHz spectrum consistent with proposed structure. Anal: calcd. forC₂₁H₂₇NO₂S+0.2H₂O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60;N, 3.98.

[0049] Step 11: Preparation of phenylmethylα-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzenepropanoate

[0050] The title compound in Step 10 (0.5 g, 1.4 mmol) was dissolved inmethanol (7 mL) and, while cooling with ice, oxone (potassiumperoxomonosulfate) (1.3 g) in water (6 mL) were added and the whole wasstirred at room temperature overnight. The solution was diluted withwater and extracted with methylene chloride, and the extracts were dried(Na₂SO₄) and concentrated by evaporation. The residue was purified byflash chromatography on silica gel, eluting with 20:1 CH₂Cl₂:MeOH togive pure title compound as white powder (400 mg, 73%). ¹H NMR: 300 MHzspectrum consistent with proposed structure. Anal: calcd. forC₂₁H₂₇NO₄S: C, 64.76; H, 6.99; N, 3.60. Found: C, 64.01; H, 6.88; N,3.41.

[0051] Step 12: Preparation ofα-[[[2-(dimethylamino)ethyl]sulfonyl]methyl] benzenepropanoic acid

[0052] The title compound of Step 11 (150 mg, 0.4 mmol) was debenzylatedin ethanol with 5 psi H₂ at room temperature for 1.5 hours using 4% Pd/Ccatalyst. After filtering, the solvent was stripped off to give thetitle compound as white powder (110 mg, 70% yield). ¹H NMR: 300 MHzspectrum consistent with proposed structure. Anal: calcd. forC₁₄H₂₁NO₄S: C, 56.16; H, 7.07; N, 4.68. Found: C, 55.88; H, 6.99; N,4.35.

[0053] Step 13: Preparation of α-[[[2-(dimethylamino)ethyl]thio]methyl]benzene propanoic acid sodium salt

[0054] The title compound of Step 10 is dissolved in methanol at roomtemperature and to this is added 1 molar equivalent of 1N aqueous sodiumhydroxide. This solution is allowed to stand for 2-4 hours, thenevaporated to dryness to afford the title compound. This material isused without further purification.

[0055] Step 14: Preparation of α-[[[2-(diethylamino)ethyl]sulfonyl]methyl]benzene propanoic acid

[0056] The title compound may be prepared by substituting the2-dimethylaminoethanethiol hydrochloride in Step 10 with2-diethylaminoethanethiol hydrochloride and proceeding with Steps 11 and12 to yield the title acid.

[0057] The following working Examples are provided to illustratesynthesis of Compounds 1-24 of the present invention and are notintended to limit the scope thereof. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thecompounds of the Examples. All temperatures expressed are in degreesCentigrade.

[0058] The acid of Step 12 (110 mg, 0.36 mmol) was dissolved at roomtemperature in a mixture of dimethylformamide (2 mL) and pyridine (0.4mL) and to this solution was added N,N′-disuccinimidyl carbonate (84 mg,0.33 mmol) and 4-dimethylaminopyridine (4 mg). The mixture was stirredfor 3 hours, and then the title amine of Step 6 (108 mg, 0.33 mmol) wasadded, followed by diisopropylethylamine (57 mL). This mixture wasallowed to stir at room temperature for 16 hours. The solvent was thenevaporated and the residue dissolved in ethyl acetate (10 mL). Themixture was washed successively with water, saturated sodium bicarbonateand brine. The solution was dried (Na₂SO₄) and evaporated. The residuewas purified by flash chromatography on silica gel, eluting with 96:3:1EtOAc:MeOH:NH₄OH to give the title compound as white powder (60 mg, 30%yield). ¹H NMR: 300 MHz spectrum consistent with proposed structure.Anal: calc'd. for C₃₃H₅₅N₃O₆S+0.4H₂O: C, 62.29; H, 9.11; N, 6.81. Found:C, 62.20; H, 8.86; N, 6.75.

EXAMPLE 2

[0059]

[0060] The acid of Step 13 (170 mg, 0.64 mmol) is dissolved at roomtemperature in a mixture of dimethylformamide (3 mL) and pyridine (0.6mL) and to this solution is added N,N′-disuccinimidyl carbonate (163 mg,0.64 mmol) and 4-dimethylaminopyridine (6 mg). The mixture is stirredfor 3 hours, and then the title amine of Step 6 (190 mg, 0.5 mmol) isadded, followed by diisopropylethylamine (87 mL). This mixture isallowed to stir at room temperature for 16 hours. The solvent is thenevaporated and the residue dissolved in ethyl acetate (15 mL). Themixture is washed successively with water, saturated sodium bicarbonateand brine. The solution is dried (Na₂SO₄) and evaporated. The residue ispurified by flash chromatography on silica gel to give the titlecompound.

EXAMPLE 3

[0061]

[0062] The acid of Step 14 (209 mg, 0.64 mmol) is dissolved at roomtemperature in a mixture of dimethylformamide (3 mL) and pyridine (0.6mL) and to this solution is added N,N′-disuccinimidyl carbonate (163 mg,0.64 mmol) and 4-dimethylaminopyridine (6 mg). The mixture is stirredfor 3 hours, and then the title amine of Step 6 (190 mg, 0.5 mmol) isadded, followed by diisopropylethylamine (87 mL). This mixture isallowed to stir at room temperature for 16 hours. The solvent is thenevaporated and the residue dissolved in ethyl acetate (15 mL). Themixture is washed successively with water, saturated sodium bicarbonateand brine. The solution is dried (Na₂SO₄) and evaporated. The residue ispurified by flash chromatography on silica gel to give the titlecompound.

[0063] Compounds 4-24, as shown in Table 1 below, may be synthesized byreference to the foregoing specific and general procedures for preparingcompounds of Formula I. TABLE I Example Compound No. Structure 4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

BIOLOGICAL EVALUATION Human Renin Inhibition in vitro

[0064] Compounds of Formula I were evaluated as inhibitors of humanrenin in an in vitro assay, as follows: This human renin inhibition testhas been previously described in detail [Papaioannou et al., Clinicaland Experimental Hypertension, A7(9), 1243-1257 (1985)]. Human renin wasobtained from the National Institute for Biological Standards, London.An incubation mixture was prepared containing the following components:in a total volume of 0.25 mL: 100 mM Tris-acetate buffer at pH 7.4,25×10⁻⁶ Goldblatt units of renin, 0.05 mL of plasma from humanvolunteers taking oral contraceptives, 6.0 mM Na-EDTA, 2.4 mMphenylmethyl sulfonyl fluoride, 1.5 mM 8-hydroxyquinoline, 0.4 mg/mLbovine serum albumin (BSA), and 0.024 mg/mL neomycin sulfate. Thismixture was incubated for two hours at 37° C. in the presence or absenceof renin inhibitors. The produced angiotensin I was determined byradioimmunoassay (New England Nuclear kit). Test compounds to be assayedwere dissolved in DMSO and diluted with 100 mM Tris-acetate buffer at pH7.4 containing 0.5% BSA to the appropriate concentration. The finalconcentration of organic solvent in the reaction mixture was less than1%. Control incubations at 37° C. were used to correct for effects oforganic solvent on renin activity. The in vitro enzymatic conversion ofangiotensinogen to angiotensin I was inhibited by test compounds of theinvention. The compound of Example #1 was found to inhibit human reninin vitro at an IC₅₀ of 44 nM.

[0065] Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

[0066] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

[0067] The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight. Compounds indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 400 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 200 mg of active compound per unit dosage form. Most preferred isa dosage form containing from about 3 mg to about 100 mg of activecompound per unit dose.

[0068] The dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention is selected inaccordance with a variety of factors, including the type, age, weight,sex and medical condition of the patient, the severity of the disease,the route of administration, and the particular compound employed, andthus may vary widely.

[0069] For therapeutic purposes, the compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

[0070] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A compound of Formula I:

wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein n is a numberselected from zero through five, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom linear and branched alkyl groups containing from one to about fourcarbon atoms: wherein R⁷ is a group selected from alkyl, cycloalkylalkyland aralkyl; wherein R⁸ is a group selected from hydrido, alkyl,hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and haloalkenyl;wherein each of R⁹ and R¹⁰ is a group independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl, aryl, aralkyl,haloaryl and haloaralkyl; and wherein any one of said R¹ through R¹¹groups having a substitutable position may be substituted with one ormore groups selected from alkyl, hydroxy, hydroxyalkyl, halo, alkoxy,alkoxyalkyl and alkenyl; or a pharmaceutically-acceptable salt thereof.2. Compound of claim 1 wherein each of R¹ and R¹¹ is independentlyselected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N,N-diethylaminoethyl and phenyl; wherein n is anumber selected from zero through four, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is selected from hydrido, cycloalkylalkyl,phenylalkyl, halophenylalkyl, naphthylalkyl and halonaphthylalkyl;wherein each of R⁴ and R⁶ is independently selected from hydrido andmethyl; wherein R⁵ is selected from methyl, ethyl, n-propyl, isopropyland n-butyl; wherein R⁷ is selected from cyclohexylmethyl and benzyl,either one of which may be substituted with one or more groups selectedfrom alkyl, hydroxy and alkoxy; wherein R⁸ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof. 3.Compound of claim 2 wherein each of R¹ and R¹¹ is independently selectedfrom hydrido, methyl, ethyl, n-propyl and isopropyl; wherein n is anumber selected from zero through three, inclusive; wherein x is anumber selected from zero, one and two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is independently selected from hydride and methyl;wherein R⁵ is selected from methyl, ethyl, n-propyl and isopropyl;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl,cyclohexylmethyl, allyl and vinyl; and wherein each of R⁹ and R¹⁰ isindependently selected from hydride, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclopropylmethyl, cyclopropylethyl, propylcarbonyl, ethylcarbonyl,methylcarbonyl, phenyl, benzyl, phenylethyl, monochlorophenyl,dichlorophenyl, monofluorophenyl, difluorophenyl,monochlorophenylmethyl, monochlorophenylethyl, dichlorophenylmethyl,dichlorophenylethyl, naphthyl, monofluoronaphthyl, monochloronaphthyl,naphthylmethyl, naphthylethyl, fluoronapthylmethyl andchloronaphthylethyl; or a pharmaceutically-acceptable salt thereof. 4.Compound of claim 3 wherein each of R¹ and R¹¹ is independently hydridoor methyl; wherein n is a number selected from zero through three,inclusive; wherein x is zero or two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is selected from methyl and ethyl; wherein R⁷ is cyclohexylmethyl;wherein R⁸ is selected from ethyl, n-propyl, n-butyl, isobutyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl; whereineach of R⁹ and R¹⁰ is independently selected from hydrido, methyl,ethyl, n-propyl, isopropyl, cyclopropylmethyl, phenyl, benzyl,monochlorophenyl and dichlorophenyl; or a pharmaceutically-acceptablesalt thereof.
 5. Compound of claim 4 of Formula II

wherein n is two or three; wherein x is a number selected from zero, oneand two; wherein R² is selected from hydrido, methyl, ethyl and phenyl;wherein R³ is selected from hydrido, cyclohexylmethyl, benzyl,fluorobenzyl, chlorobenzyl, naphthylmethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is methyl; wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected fromn-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl;wherein each of R⁹ and R¹⁰ is independently selected from methyl, ethyland isopropyl; or a pharmaceutically-acceptable salt thereof. 6.Compound of claim 5 selected from compounds, their tautomers, and thepharmaceutically-acceptable esters thereof, of the group consisting of


7. Compound of claim 6 which is

or a pharmaceutically-acceptable salt thereof.
 8. Compound of claim 6which is

or a pharmaceutically-acceptable salt thereof.
 9. Compound of claim 6which is

or a pharmaceutically-acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a therapeutically-effective amount of arenin-inhibiting compound and a pharmaceutically-acceptable carrier ordiluent, said renin-inhibiting compound selected from a family ofcompounds of Formula I:

wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein n is a numberselected from zero through five, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom linear and branched alkyl groups containing from one to about fourcarbon atoms; wherein R⁷ is a group selected from alkyl, cycloalkylalkyland aralkyl; wherein R⁸ is a group selected from hydrido, alkyl,hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and haloalkenyl;wherein each of R⁹ and R¹⁰ is a group independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl, aryl, aralkyl,haloaryl and haloaralkyl; and wherein any one of said R¹ through R¹¹groups having a substitutable position may be substituted with one ormore groups selected from alkyl, hydroxy, hydroxyalkyl, halo, alkoxy,alkoxyalkyl and alkenyl; or a pharmaceutically-acceptable salt thereof.11. The composition of claim 10 wherein each of R¹ and R¹¹ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N,N-diethylaminoethyl and phenyl; wherein n is anumber selected from zero through four, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is selected from hydrido, cycloalkylalkyl,phenylalkyl, halophenylalkyl, naphthylalkyl and halonaphthylalkyl;wherein each of R⁴ and R⁶ is independently selected from hydrido andmethyl; wherein R⁵ is selected from methyl, ethyl, n-propyl, isopropyland n-butyl; wherein R⁷ is selected from cyclohexylmethyl and benzyl,either one of which may be substituted with one or more groups selectedfrom alkyl, hydroxy and alkoxy; wherein R⁸ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof. 12.The composition of claim 11 wherein each of R¹ and R¹¹ is independentlyselected from hydrido, methyl, ethyl, n-propyl and isopropyl; wherein nis a number selected from zero through three, inclusive; wherein x is anumber selected from zero, one and two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is independently selected from hydrido and methyl;wherein R⁵ is selected from methyl, ethyl, n-propyl and isopropyl;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl,cyclohexylmethyl, allyl and vinyl; and wherein each of R⁹ and R¹⁰ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclopropylmethyl, cyclopropylethyl, propylcarbonyl, ethylcarbonyl,methylcarbonyl, phenyl, benzyl, phenylethyl, monochlorophenyl,dichlorophenyl, monofluorophenyl, difluorophenyl,monochlorophenylmethyl, monochlorophenylethyl, dichlorophenylmethyl,dichlorophenylethyl, naphthyl, monofluoronaphthyl, monochloronaphthyl,naphthylmethyl, naphthylethyl, fluoronapthylmethyl andchloronaphthylethyl; or a pharmaceutically-acceptable salt thereof. 13.The composition of claim 12 wherein each of R¹ and R¹¹ is independentlyhydrido or methyl; wherein n is a number selected from zero throughthree, inclusive; wherein x is zero or two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is selected from methyl and ethyl; wherein R⁷ is cyclohexylmethyl;wherein R⁸ is selected from ethyl, n-propyl, n-butyl, isobutyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl; whereineach of R⁹ and R¹⁰ is independently selected from hydrido, methyl,ethyl, n-propyl, isopropyl, cyclopropylmethyl, phenyl, benzyl,monochlorophenyl and dichlorophenyl; or a pharmaceutically-acceptablesalt thereof.
 14. The composition of claim 13 wherein saidrenin-inhibiting compound is of Formula II:

wherein n is two or three; wherein x is a number selected from zero, oneand two; wherein R² is selected from hydrido, methyl, ethyl and phenyl;wherein R³ is selected from hydrido, cyclohexylmethyl, benzyl,fluorobenzyl, chlorobenzyl, naphthylmethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein R⁷ is cyclohexylmethyl; wherein R⁵ ismethyl; wherein R⁸ is selected from n-propyl, isobutyl, cyclopropyl,cyclopropylmethyl, allyl and vinyl; wherein each of R⁹ and R¹⁰ isindependently selected from methyl, ethyl and isopropyl; or apharmaceutically-acceptable salt thereof.
 15. The composition of claim14 wherein said renin-inhibiting compound is

or a pharmaceutically-acceptable salt thereof.
 16. The composition ofclaim 14 wherein said renin-inhibiting compound is

or a pharmaceutically-acceptable salt thereof.
 17. The composition ofclaim 14 wherein said renin-inhibiting compound is

or a pharmaceutically-acceptable salt thereof.
 18. A therapeutic methodfor treating a circulatory-related disorder, said method comprisingadministering to a hypertensive patient a therapeutically-effectiveamount of a compound of Formula I:

wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein n is a numberselected from zero through five, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom linear and branched alkyl groups containng from one to about fourcarbon atoms;; wherein R⁷ is a group selected from alkyl,cycloalkylalkyl and aralkyl; wherein R⁸ is a group selected fromhydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl andhaloalkenyl; wherein each of R⁹ and R¹⁰ is a group independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl,aryl, aralkyl, haloaryl and haloaralkyl; and wherein any one of said R¹through R¹¹ groups having a substitutable position may be substitutedwith one or more groups selected from alkyl, hydroxy, hydroxyalkyl,halo, alkoxy, alkoxyalkyl and alkenyl; or a pharmaceutically-acceptablesalt thereof.
 19. The method of claim 18 wherein each of R¹ and R¹¹ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N,N-diethylaminoethyl and phenyl; wherein n is anumber selected from zero through four, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is selected from hydrido, cycloalkylalkyl,phenylalkyl, halophenylalkyl, naphthylalkyl and halonaphthylalkyl;wherein each of R⁴ and R⁶ is independently selected from hydrido andmethyl; wherein R⁵ is selected from methyl, ethyl, n-propyl, iso-propyland n-butyl ; wherein R⁷ is selected from cyclohexylmethyl and benzyl,either one of which may be substituted with one or more groups selectedfrom alkyl, hydroxy and alkoxy; wherein R⁸ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof. 20.The method of claim 19 wherein each of R¹ and R¹¹ is independentlyselected from hydrido, methyl, ethyl, n-propyl and isopropyl; wherein nis a number selected from zero through three, inclusive; wherein x is anumber selected from zero, one and two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is independently selected from hydrido and methyl;wherein R⁵ is selected from methyl, ethyl, n-propyl and isopropyl;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl,cyclohexylmethyl, allyl and vinyl; and wherein each of R⁹ and R¹⁰ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclopropylmethyl, cyclopropylethyl, propylcarbonyl, ethylcarbonyl,methylcarbonyl, phenyl, benzyl, phenylethyl, monochlorophenyl,dichlorophenyl, monofluorophenyl, difluorophenyl,monochlorophenylmethyl, monochlorophenylethyl, dichlorophenylmethyl,dichlorophenylethyl, naphthyl, monofluoronaphthyl, monochloronaphthyl,naphthylmethyl, naphthylethyl, fluoronapthylmethyl andchloronaphthylethyl; or a pharmaceutically-acceptable salt thereof. 21.The method of claim 20 wherein each of R¹ and R¹¹ is independentlyhydrido or methyl; wherein n is a number selected from zero throughthree, inclusive; wherein x is zero or two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is selected from methyl and ethyl; wherein R⁷ is cyclohexylmethyl;wherein R⁸ is selected from ethyl, n-propyl, n-butyl, isobutyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl; whereineach of R⁹ and R¹⁰ is independently selected from hydrido, methyl,ethyl, n-propyl, isopropyl, cyclopropylmethyl, phenyl, benzyl,monochlorophenyl and dichlorophenyl; or a pharmaceutically-acceptablesalt thereof.
 22. The method of claim 21 wherein said compound is ofFormula II:

wherein n is two or three; wherein x is a number selected from zero, oneand two; wherein R² is selected from hydrido, methyl, ethyl and phenyl;wherein R³ is selected from hydrido, cyclohexylmethyl, benzyl,fluorobenzyl, chlorobenzyl, naphthylmethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is methyl; wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected fromn-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl;wherein each of R⁹ and R¹⁰ is independently selected from methyl, ethyland isopropyl; or a pharmaceutically-acceptable salt thereof.
 23. Themethod of claim 22 wherein said compound is

or a pharmaceutically-acceptable salt thereof.
 24. The method of claim22 wherein said compound is

or a pharmaceutically-acceptable salt thereof.
 25. The method of claim22 wherein said compound is

or a pharmaceutically-acceptable salt thereof.
 26. The method of claim18 wherein said circulatory-related disorder is a cardiovasculardisorder.
 27. The method of claim 26 wherein said cardiovasculardisorder is a hypertension.
 28. The method of claim 26 wherein saidcardiovascular disorder is congestive heart failure.
 29. The method ofclaim 18 wherein said circulatory-related disorder is glaucoma.
 30. Themethod of claim 18 wherein said circulatory-related disorder is renalfailure.